Identification of Haemophilus influenzae clones associated with invasive disease a decade after introduction of H. influenzae serotype b vaccination in Italy.
The introduction of Haemophilus influenzae serotype b (Hib) conjugate vaccines has changed the epidemiology of invasive H. influenzae disease, with a shift in the predominant serotype from Hib to nonencapsulated H. influenzae (ncHi). The objective of this study was to identify the genotypes/clones associated with invasive H. influenzae disease in Italy. Eighty-seven H. influenzae strains isolated in the years 2009 to 2011 within the National Surveillance of Invasive Bacterial Disease program were analyzed. Strains were characterized by serotyping, antimicrobial susceptibility testing, and multilocus sequence typing (MLST). Genetic polymorphisms in the bla(TEM) gene promoter region as well as the occurrence of both adhesin genes (hmwA and hia) and the IgA1 protease-encoding gene (igaB) were also investigated. Of 87 strains, 67 were ncHi and 20 were encapsulated. Eleven strains were β-lactamase positive, harboring the bla(TEM) gene. Most bla(TEM) genes (10/11) were associated with a Pdel promoter region exhibiting a 135-bp deletion; the remaining strain possessed the Pa/Pb overlapping promoter. MLST analysis showed that encapsulated isolates were clonal, with each serotype sharing a few related sequence types (STs). Forty-six different STs were identified among the 67 ncHi strains. Despite this heterogeneity, a group of closely related STs (ST103, ST139, and ST145) encompassed almost 25% of all ncHi strains and 45.5% of the β-lactamase producers carrying the Pdel promoter. These major ST clones were found to be associated with the hmwA gene but not with the igaB gene. To conclude, although the heterogeneity of the ncHi population was confirmed, diffusion of major successful ST clones was documented.


Monoamine acid metabolites and cerebrospinal fluid dynamics in normal pressure hydrocephalus: preliminary results.
Lumbar and ventricular CSF concentration of homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA) have been determined in 13 patients admitted to hospital for suspected normal pressure hydrocephalus. Low values of HVA in lumbar CSF were found in all patients with reduced CSF absorption and CSF flow inversion. The HVA lumbar concentration remained low after shunt procedure; it increased if obstruction of the shunt occurred. The ventricular CSF concentration of HVA was normal before surgery; it became higher, in two cases, after surgery. No important variations were found in the lumbar and ventricular CSF concentration of 5-HIAA. The possible mechanisms and diagnostic value of these findings are discussed.


[Endothelial dysfunction as a primary disorder in vascular diseases].
Endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium derived relaxing factors, mainly nitric oxide, a potent vasodilator, inhibitor of platelet aggregation, monocyte adhesion and smooth muscle proliferation. In addition, the endothelium may increase the release of NO in response to humoral stimulation by vasoactive substances such as acetylcholine, bradykinin or substance P. Although the endothelium releases a number of products, no single blood test has yet proved useful to determine normal endothelial function or as early abnormalities. The most useful test of endothelial function relies on the measurement of endothelium-dependent dilatation in response to pharmacological or physiologic stimuli. The alteration of this response is known as endothelial dysfunction and has been observed in a variety of circumstances related to cardiovascular risk. This review summarizes the evidence that sustains this association and emphasizes the clinical utility of assessing endothelial function presenting two clinical cases of hypercholesterolemia in which a high-resolution vascular ultrasound in the brachial artery was used.


Customer satisfaction.
This paper seeks to present an analysis of the literature examining objective information concerning the subject of customer service, as it applies to the current medical practice. Hopefully, this information will be synthesized to generate a cogent approach to correlate customer service with quality. Articles were obtained by an English language search of MEDLINE from January 1976 to July 2005. This computerized search was supplemented with literature from the author's personal collection of peer-reviewed articles on customer service in a medical setting. This information was presented in a qualitative fashion. There is a significant lack of objective data correlating customer service objectives, patient satisfaction and quality of care. Patients present predominantly for the convenience of emergency department care. Specifics of satisfaction are directed to the timing, and amount of "caring". Demographic correlates including symptom presentation, practice style, location and physician issues directly impact on satisfaction. It is most helpful to develop a productive plan for the "difficult patient", emphasizing communication and empathy. Profiling of the customer satisfaction experience is best accomplished by examining the specifics of satisfaction, nature of the ED patient, demographic profile, symptom presentation and physician interventions emphasizing communication--especially with the difficult patient. The current emergency medicine customer service dilemmas are a complex interaction of both patient and physician factors specifically targeting both efficiency and patient satisfaction. Awareness of these issues particular to the emergency patient can help to maximize efficiency, minimize subsequent medicolegal risk and improve patient care if a tailored management plan is formulated.


Common hyperpigmentation disorders in adults: Part I. Diagnostic approach, café au lait macules, diffuse hyperpigmentation, sun exposure, and phototoxic reactions.
The cause of hyperpigmentation usually is traced to the activity and presence of melanocytes. Café au lait macules may be solitary benign findings or may indicate the presence of neurofibromatosis with its associated complications. Diffuse hyperpigmentation should prompt a search for offending medications or systemic diseases such as hemochromatosis, hyperthyroidism, and Addison's disease. In these instances, the hyperpigmentation may be ameliorated by discontinuing offending medications, performing serial phlebotomy in patients with hemochromatosis, instituting cause-specific treatments in patients with hyperthyroidism, and replacing deficient glucocorticoids and mineralocorticoids in patients with Addison's disease. Cosmetic treatment with bleaching agents or lasers can be used to decrease pigmentation of ephelides (freckles) and lentigines.


Diatoms.org: supporting taxonomists, connecting communities.
Consistent identification of diatoms is a prerequisite for studying their ecology, biogeography, and successful application as environmental indicators. However, taxonomic consistency among observers has been difficult to achieve, because taxonomic information is scattered across numerous literature sources, presenting challenges to the diatomist. First, literature is often inaccessible because of cost, or its location in journals that are not widely circulated. Second, taxonomic revisions of diatoms are taking place faster than floras can be updated. Finally, taxonomic information is often contradictory across literature sources. These issues can be addressed by developing a content creation community dedicated to making taxonomic, ecological, and image-based data freely available for diatom researchers. Diatoms.org represents such a content curation community, providing open, online access to a vast amount of recent and historical information on North American diatom taxonomy and ecology. The content curation community aggregates existing taxonomic information, creates new content, and provides feedback in the form of corrections and notice of literature with nomenclatural changes. The website not only addresses the needs of experienced diatom scientists for consistent identification, but is also designed to meet users at their level of expertise, including engaging the lay public in the importance of diatom science. The website now contains over 1000 species pages contributed by over 100 content contributors, from students to established scientists. The project began with the intent to provide accurate information on diatom identification, ecology, and distribution using an approach that incorporates engaging design, user feedback, and advanced data access technology. In retrospect, the project that began as an "extended electronic book" has emerged not only as a means to support taxonomists, but for practitioners to communicate and collaborate, expanding the size of and benefits to the content curation community. In this paper, we outline the development of diatoms.org, document key elements of the project, examine ongoing challenges, and consider the unexpected emergent properties, including the value of diatoms.org as a source of data. Ultimately, if the field of diatom taxonomy, ecology, and biodiversity is to be relevant, a new generation of taxonomists needs to be trained and employed using new tools. We propose that diatoms.org is in a key position to serve as a hub of training and continuity for the study of diatom biodiversity and aquatic conditions.


Endotracheal Intubation Among the Critically Ill: Protocol for a Multicenter, Observational, Prospective Study.
Endotracheal intubation can occur in up to 60% of critically ill patients. Despite the frequency with which endotracheal intubation occurs, the current practice is largely unknown. This is relevant, as advances in airway equipment (ie, video laryngoscopes) have become more prevalent, leading to possible improvement of care delivered during this process. In addition to new devices, a greater emphasis on airway plans and choices in sedation have evolved, although the influence on patient morbidity and mortality is largely unknown. This study aims to derive and validate prediction models for immediate airway and hemodynamic complications of intensive care unit intubations. A multicenter, observational, prospective study of adult critically ill patients admitted to both medical and surgical intensive care units (ICUs) was conducted. Participating ICU sites were located throughout eight health and human services regions of the United States for which endotracheal intubation was needed. A steering committee composed of both anesthesia and pulmonary critical care physicians proposed a core set of data variables. These variables were incorporated into a data collection form to be used within the multiple, participating ICUs across the United States during the time of intubation. The data collection form consisted of two basic components, focusing on airway management and hemodynamic management. The form was generated using RedCap and distributed to the participating centers. Quality checks on the dataset were performed several times with each center, such that they arrived at less than 10% missing values for each data variable; the checks were subsequently entered into a database. The study is currently undergoing data analysis. Results are expected in November 2018 with publication to follow thereafter. The study protocol has not yet undergone peer review by a funding body. The overall goal of this multicenter prospective study is to develop a scoring system for peri-intubation, hemodynamic, and airway-related complications so we can stratify those patients at greatest risk for decompensation as a result of these complications. This will allow critical care physicians to be better prepared in addressing these occurrences and will allow them to improve the quality of care delivered to the critically ill. ClinicalTrials.gov NCT02508948; https://clinicaltrials.gov/ct2/show/NCT02508948 (Archived by WebCite at http://www.webcitation.org/73Oj6cTFu). RR1-10.2196/11101.


The Discovery, Mechanisms, and Evolutionary Impact of Anti-CRISPRs.
Bacteria and archaea use CRISPR-Cas adaptive immune systems to defend themselves from infection by bacteriophages (phages). These RNA-guided nucleases are powerful weapons in the fight against foreign DNA, such as phages and plasmids, as well as a revolutionary gene editing tool. Phages are not passive bystanders in their interactions with CRISPR-Cas systems, however; recent discoveries have described phage genes that inhibit CRISPR-Cas function. More than 20 protein families, previously of unknown function, have been ascribed anti-CRISPR function. Here, we discuss how these CRISPR-Cas inhibitors were discovered and their modes of action were elucidated. We also consider the potential impact of anti-CRISPRs on bacterial and phage evolution. Finally, we speculate about the future of this field.


Loss of pRB causes centromere dysfunction and chromosomal instability.
Chromosome instability (CIN) is a common feature of tumor cells. By monitoring chromosome segregation, we show that depletion of the retinoblastoma protein (pRB) causes rates of missegregation comparable with those seen in CIN tumor cells. The retinoblastoma tumor suppressor is frequently inactivated in human cancers and is best known for its regulation of the G1/S-phase transition. Recent studies have shown that pRB inactivation also slows mitotic progression and promotes aneuploidy, but reasons for these phenotypes are not well understood. Here we describe the underlying mitotic defects of pRB-deficient cells that cause chromosome missegregation. Analysis of mitotic cells reveals that pRB depletion compromises centromeric localization of CAP-D3/condensin II and chromosome cohesion, leading to an increase in intercentromeric distance and deformation of centromeric structure. These defects promote merotelic attachment, resulting in failure of chromosome congression and an increased propensity for lagging chromosomes following mitotic delay. While complete loss of centromere function or chromosome cohesion would have catastrophic consequences, these more moderate defects allow pRB-deficient cells to proliferate but undermine the fidelity of mitosis, leading to whole-chromosome gains and losses. These observations explain an important consequence of RB1 inactivation, and suggest that subtle defects in centromere function are a frequent source of merotely and CIN in cancer.


Modelling low-energy electron-molecule capture processes.
Cross sections and rate coefficients for capture of low-energy electrons with polar and polarizable target molecules are calculated in the framework of Fabrikant and Hotop's extended version of the Vogt-Wannier model and an extension of this approach is given in the present article. Analytical approximations are derived in order to facilitate the application to experiments. A comparison with a selection of experimental electron attachment rate coefficients provides insight into the competition between anion formation through electron capture and scattering processes which do not follow this pathway.


[Efficacy of shock-wave therapy in the treatment of chronic ischemic heart failure].
Shock-wave therapy (SWT) has proved its efficacy and safety in a number of studies in stable effort angina. Twenty-four patients (20 men, 4 women; mean age 63.3 +/- 6.1 years) with chronic heart failure (CHF) of ischemic origin (>6 months after AMI) and left ventricular (LV) ejection fraction (EF) <40% received SWT in addition to their stable treatment. SWT was performed in 9 sessions with 100 shocks per spot in viable segments detected by low dose dobutamine stress echocardiography. Patients were examined at baseline and at 3 and 6 months after SWT. Troponin T level was measured after each week of treatment. Class of CHF significantly decrease from 2.2 +/- 0.8 to 1.7 +/- 0.7 at 3 and at 6 months after SWT (p<0.01). Six-minute walk test improved from 414 +/- 141 to 509 +/- 141 and 538 +/- 116 m (p<0.01) at 3 and 6 months, respectively. Significant augmentation of LVEF at rest was noted at 3 and 6 months after SWT (from 32.2 +/- 6.0 to 34.8 +/- 9.6 and 37.7 +/- 9.5, respectively p=0.03). Troponin T was negative in all cases. Significant increase of LV longitudinal deformation was registered at 6 months (from -8.84 +/- 0.38 to -9.72 +/- -0.44%, p<0.01) what evidenced for improvement of LV contractility. The latter was a result of restored hibernating segments function (longitudinal deformation of these segments rose from initial -7.52 +/- -0.5 to -9.18 +/- 0.53 and -9.63 +/- 0.59% at 3 and 6 months after SWT, respectively, p<0.01). In patients with CHF SWT caused significant clinical improvement as well as increases in LV EF and distance walked during 6-min walk test. These results justify conduct of a placebo controlled study.


Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis.
The articular surface plays an essential role in load transfer across the joint, and conditions that produce increased load transfer or altered patterns of load distribution accelerate the development of osteoarthritis (OA). Current knowledge segregates the risk factors into two fundamental mechanisms related to the adverse effects of "abnormal" loading on normal cartilage or "normal" loading on abnormal cartilage. Although chondrocytes can modulate their functional state in response to loading, their capacity to repair and modify the surrounding extracellular matrix is limited in comparison to skeletal cells in bone. This differential adaptive capacity underlies the more rapid appearance of detectable skeletal changes, especially after acute injuries that alter joint mechanics. The imbalance in the adaptation of the cartilage and bone disrupts the physiological relationship between these tissues and further contributes to OA pathology. This review focuses on the specific articular cartilage and skeletal features of OA and the putative mechanisms involved in their pathogenesis.


MicroRNA-126-3P targets PIK3R2 to ameliorate autophagy and apoptosis of cortex in hypoxia-reoxygenation treated neonatal rats.
Here, we explored a possible mechanism of microRNA-126-3p (miR-126-3p) on neonatal rats with hypoxia-reoxygenation injury (HI). After administering HI to newborn Sprague-Dawley rats, the expression of miR-126-3p in the brain injury was assessed by RT-PCR. A miR-126-3p mimic and inhibitor were treated in the HI neonatal rats. The water maze test, TTC, HE, Nissl and TUNEL staining were separately implemented to test the effects of miR-126-3p on the HI-treated neonatal rats. At the same time, the phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) expression in the damaged cortex region was analyzed. In vitro, cortical neurons were cultured and treated with oxygen and glucose deprivation (OGD), then transfected miR-126-3p mimic, PIK3R2 overexpression lentivirus vector or silence of PIK3R2. The cell viability was observed by CCK-8. The autophagy of neurons was detected by acridine orange staining. In contrast to the sham-operated rats, the miR-126-3p expression significantly decreased, but PIK3R2 expression markedly rose in the cortex of HI rats. Injection of miR-126-3p mimic raised the learning and memory abilities through down-regulating the cerebral ischemic area, improving pathological damage of the cortex, reducing the neurons apoptosis of the cortex and down-regulating the autophagy-related and apoptosis-related proteins. Overexpression of PIK3R2, a miR-126-3p target, may reduce cell viability and boost autophagy and apoptosis. Silence of PIK3R2 promoted cell viability and inhibited cell apoptosis and autophagy. The consequences of miR-126-3p were comparable to those of PIK3R2 silencing. A new therapeutic target for HI injury in newborn rats is provided by the overexpression of miR-126-3p, which inhibits autophagy and death of cortical neurons by targeting PIK3R2 in HI-treated neonatal rats.


[Fracture diagnosis with digital luminescence radiography].
Conventional screen-film radiographs were compared with storage phosphorus images concerning diagnostic performance in traumatologic radiography. We used an image pool of 106 radiographs including 50 conventionally and 56 digitally recorded images. The images were reviewed by four experienced radiologists. Detectability of fractures was coded in a five-point scale of confidence and analysed by ROC statistics. Furthermore the image quality and the optical density was compared. Digital images are superior under difficult exposure conditions and offer advantages by additional image processing and documentation. For some indications (follow-up, functional examination), reduced x-ray exposure is tolerable. The detectability of subtle lesions, which is essential for the primary diagnosis of fractures was significantly better by conventional radiography.


Use of labeling pattern of liver glutamate to calculate rates of citric acid cycle and gluconeogenesis.
The use of the labeling pattern of hepatic glutamate during infusion of L-[3-13C]- or [3-14C]lactate to calculate rates of citric acid cycle activity and gluconeogenesis has been proposed. We tested the validity of this approach by perfusing isolated rat livers (48 h starved) with pyruvate and lactate (10% enriched with [3-13C]lactate) without (control) or with infusion of glucagon (to inhibit pyruvate kinase), mercaptopicolinate (to inhibit phosphoenolpyruvate carboxykinase), or dichloroacetate (to stimulate pyruvate dehydrogenase). Compared with control experiments, glucagon increased glucose output (P < 0.05) and decreased the calculated flux through pyruvate kinase (P < 0.05). Mercaptopicolinate almost totally suppressed glucose production and dramatically reduced the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase (P < 0.001). Dichloroacetate moderately increased the calculated flux through pyruvate dehydrogenase (P < 0.05). In experiments with perfused livers from fed rats, the calculated gluconeogenic rate and flux through phosphoenolpyruvate carboxykinase were very low compared with control experiments (P < 0.001), whereas the pyruvate dehydrogenase flux was increased (P < 0.05). Therefore, the expected modifications of the citric acid cycle activity and gluconeogenic rate were clearly detected using the labeling pattern of glutamate to calculate these metabolic rates. Except for the perfusions with mercaptopicolinate, the dilution by isotopic exchange in the oxaloacetate pool calculated from the model agreed with the actual dilution of enrichment between liver pyruvate and phosphoenolpyruvate. The present results support the validity of this approach to trace liver metabolism.


Adolescent health and high school dropout: a prospective cohort study of 9000 Norwegian adolescents (the Young-HUNT).
High school dropout is of major concern in the western world. Our aims were to estimate the risk of school dropout in adolescents following chronic somatic disease, somatic symptoms, psychological distress, concentration difficulties, insomnia or overweight and to assess to which extent the family contributes to the association between health and school dropout. A population of 8950 school-attending adolescents (13-21 years) rated their health in the Young-HUNT 1 Study (90% response rate) in 1995-1997. High school dropout or completion, was defined with the Norwegian National Education Database in the calendar year the participant turned 24 years old. Parental socioeconomic status was defined by using linkages to the National Education Database, the National Insurance Administration and the HUNT2 Survey. We used logistic regression to estimate odds ratios and risk differences of high school dropout, both in the whole population and among siblings within families differentially exposed to health problems. All explored health dimensions were strongly associated with high school dropout. In models adjusted for parental socioeconomic status, the risk differences of school dropout according to health exposures varied between 3.6% (95% CI 1.7 to 5.5) for having ≥ 1 somatic disease versus none and 11.7% (6.3 to 17.0) for being obese versus normal weight. The results from the analyses comparing differentially exposed siblings, confirmed these results with the exception of weaker associations for somatic diseases and psychological distress. School dropout was strongly clustered within families (family level conditional intraclass correlation 0.42). Adolescent health problems are markers for high school dropout, independent of parental socioeconomic status. Although school dropout it strongly related to family-level factors, also siblings with poor health have reduced opportunity to complete high school compared to healthy siblings. Public health policy should focus on ensuring young people with poor health the best attainable education.


Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 1--ELIOT.
Two randomized intraoperative radiation therapy trials for early-stage breast cancer were recently published. The ELIOT Trial used electrons (IOERT), and the TARGIT-A Trial Update used 50-kV X-rays (IORT). These studies were compared for similarities and differences. The results were analyzed and used to determine which patients might be suitable for single-dose treatment. The primary sources of data were the ELIOT Trial and TARGIT-A Trial, as well as a comprehensive analysis of the peer-reviewed literature of accelerated partial breast irradiation (APBI) using 50-kV X-rays or electrons. Studies published or presented prior to March 2014 were analyzed for efficacy, patient restrictions, complications, and outcome. With a median follow-up of 5.8 years, the 5-year recurrence rates for ELIOT versus external beam radiation therapy (EBRT) patients were 4.4 % and 0.4 %, respectively, p = .0001. A low-risk ELIOT group was identified with a 5-year recurrence rate of 1.5 %. With a median follow-up of 29 months, the 5-year recurrence rates for the TARGIT-A versus EBRT patients were 3.3 % and 1.3 %, respectively, p = .042. With 5.8 years of median follow-up, IOERT appears to have a subset of low-risk women for whom IOERT is acceptable. With 29 months of median follow-up the results of IORT with 50-kV devices are promising, but longer follow-up data are required. At the current time, single-fraction IOERT or IORT patients should be treated under strict institutional protocols.


A pilot study to assess compliance and impact of health warnings on tobacco products in the Udupi district of Karnataka State, India.
The Government of India has taken several steps to reduce tobacco use, including legislation in the Cigarettes and Other Tobacco Products Act (COTPA) requiring health warnings on tobacco products. This study assessed compliance with the legislation on warnings, and awareness of these warnings and their perceived impact in preventing tobacco uptake among college students in a district of Karnataka, India. This study consisted of two components, pack collection and a survey. For the first, tobacco packs were obtained from all tobacco selling shops in an urban and a rural locality in the Karkala block of Udupi district. Empty cigarette packs were collected from shops, and full packs were purchased if empty packs were not available . The packs were collected to measure their dimensions, as per the Tobacco Pack Surveillance System guidelines, and assessed for compliance, as per COTPA. For the second component of the study, a questionnaire was distributed to each college student to fill in; this was done to assess awareness of the new warnings at the time of the pilot survey, knowledge of harms, and perceptions of the warnings in reducing tobacco uptake. We collected 26 tobacco packs. Two (8%) packs had warnings that were the correct size (85% of the main display areas), 15 (58%) packs had clear and legible warnings, and 18 (69%) packs had warning messages in the appropriate language. In the student survey, 60% of males and 52% of females indicated that they would not start using any tobacco products on seeing the new warnings. Only a few studies other than our pilot study have assessed compliance with legislation on health warnings in low- or middle-income countries. Although health warnings were perceived as a deterrent to tobacco use among students, compliance with national legislation in this pilot study was found to be low.


Relationship of neuropsychological performance to functional status in nursing home residents and community-dwelling older adults.
The authors examined the association between neuropsychological tests of executive functioning and episodic memory and functional disability in nursing home residents versus community-dwelling older adults. The neuropsychological performance of 96 residents from the Jewish Home and Hospital, Bronx, NY and 192 gender- and age-matched older adults from residential communities in the New York metropolitan area was assessed in eight tasks (Word List Recall, Delayed Recall, Recognition, Boston Naming, Verbal Fluency, Trailmaking A and B, and Digit Symbol Substitution). Functional status was derived from the Clinical Dementia Rating scale (CDR) extended activities of daily living scores. Regression analyses were performed to test for differences in cross-sectional age-gradients for cognitive and functional status between nursing home residents and community-dwellers. Furthermore, regression analyses, controlling for age, gender, dementia status, and education, were performed to determine the association between neuropsychological performance and functional status, comparing domains of executive functioning and memory. Community-dwelling older adults showed age-related deficits both in overall cognitive status and functional disability, which were larger in nursing home residents. Executive functioning was associated with functional disability beyond the effects of age, gender, education, dementia status, residential status, overall cognitive status, memory, and cognitive speed. Executive functioning is associated with functional deficits in both community-dwelling older adults and nursing home residents. Measures of executive functioning may prove useful in intervention studies aimed at delaying institutionalization.


Finite element analysis of implant-supported prosthesis with pontic and cantilever in the posterior maxilla.
The aim of this study was to evaluate the influence of pontic and cantilever designs (mesial and distal) on 3-unit implant-retained prosthesis at maxillary posterior region verifying stress and strain distributions on bone tissue (cortical and trabecular bones) and stress distribution in abutments, implants and fixation screws, under axial and oblique loadings, by 3D finite element analysis. Each model was composed of a bone block presenting right first premolar to the first molar, with three or two external hexagon implants (4.0 × 10 mm), supporting a 3-unit splinted dental fixed dental prosthesis with the variations: M1 - three implants supporting splinted crowns; M2 - two implants supporting prosthesis with central pontic; M3 - two implants supporting prosthesis with mesial cantilever; M4 - two implants supporting prosthesis with distal cantilever. The applied forces were 400 N axial and 200 N oblique. The von Mises criteria was used to evaluate abutments, implants and fixation screws and maximum principal stress and microstrain criteria were used to evaluate the bone tissue. The decrease of the number of implants caused an unfavorable biomechanical behavior for all structures (M2, M3, M4). For two implant-supported prostheses, the use of the central pontic (M2) showed stress and strain distributions more favorable in the analyzed structures. The use of cantilever showed unfavorable biomechanical behavior (M3 and M4), mainly for distal cantilever (M4). The use of three implants presented lower values of stress and strain on the analyzed structures. Among two implant-supported prostheses, prostheses with cantilever showed unfavorable biomechanical behavior in the analyzed structures, especially for distal cantilever.


Glomerular deposition of food antigens in IgA nephropathy.
Recently, we reported on the importance of food antigens on the pathogenesis of an experimentally-induced model of, and some patients with, IgA nephropathy. In this paper, the glomerular deposition of food antigens (casein, lactalbumin, peanut protein, soy bean protein, rice protein, ovalbumin) was investigated by an immunofluorescence technique in 28 patients with IgA nephropathy and 32 controls (ten with lupus nephritis, three with Henoch-Schoenlein purpura nephritis and 19 with other glomerulonephritis). Glomerular IgA deposition was demonstrated in all IgA nephropathy and Henoch-Schoenlein purpura nephritis, and in four lupus nephritis. Positive findings of food antigens, observed as mesangial pattern, were obtained in eleven cases (39.3%) with casein, 21 (75.0%) with soy bean protein and one (3.6%) with rice protein in IgA nephropathy, even though no such findings were seen in the control group. Eleven of 28 patients with IgA nephropathy were positive with soy bean protein alone, nine were positive with soy bean protein + casein, one was positive with soy bean protein + casein + rice protein, and one was positive with casein alone. The deposition of food antigens was not observed in six cases only. Furthermore, no correlation was noted between the deposition of food antigens and the deposition of IgA1, IgA2 or J chain, in vitro binding of the secretory component, or histopathological grades. These results suggest that the exact meanings of glomerular deposition are unclear. Food antigens are postulated, however, as possibly participating strongly in the pathogenesis and as being localized in the glomerular mesangium as an antigen in some patients with IgA nephropathy.


Sparse image reconstruction on the sphere: implications of a new sampling theorem.
We study the impact of sampling theorems on the fidelity of sparse image reconstruction on the sphere. We discuss how a reduction in the number of samples required to represent all information content of a band-limited signal acts to improve the fidelity of sparse image reconstruction, through both the dimensionality and sparsity of signals. To demonstrate this result, we consider a simple inpainting problem on the sphere and consider images sparse in the magnitude of their gradient. We develop a framework for total variation inpainting on the sphere, including fast methods to render the inpainting problem computationally feasible at high resolution. Recently a new sampling theorem on the sphere was developed, reducing the required number of samples by a factor of two for equiangular sampling schemes. Through numerical simulations, we verify the enhanced fidelity of sparse image reconstruction due to the more efficient sampling of the sphere provided by the new sampling theorem.


Probing the importance and potential roles of the binding of the PH-domain protein Boi1 to acidic phospholipids.
The related proteins Boi1 and Boi2, which appear to promote polarized growth in S. cerevisiae, both contain a PH (pleckstrin homology) and an SH3 (src homology 3) domain. Previously, we gained evidence that a PH domain-bearing segment of Boi1, which we call Boi1-PH, is sufficient and necessary for function. In the current study, we investigate the binding of Boi1's PH domain to the acidic phospholipids PIP2 (phosphatidylinositol-4,5-bisphosphate) and PS (phosphatidylserine). Boi1-PH co-sediments with PS vesicles. It does so more readily when these vesicles contain a small amount of PIP2. Boi1-PH is degraded in yeast extracts in a manner that is stimulated by PIP2. Amino-acid substitutions that diminish binding to PIP2 and PS impair Boi1 function. Fusion to a myristoyl group-accepting sequence improves to different degrees the ability of these different mutant versions of Boi1-PH to function. Boi1 and Boi2 are localized to the periphery of buds during much of the budding cycle and to necks late in the cell cycle. Amino-acid substitutions that diminish binding to PIP2 and PS impair localization of Boi1 to the bud, but do not affect the localization of Boi1 to the neck. Conversely, a mutation in the SH3 domain prevents the localization of Boi1 to the neck, but does not impair localization to the bud. Boi1's PH domain binds to acidic phospholipids, and this binding appears to be important for Boi1 function. The main role of binding to PS may simply be to promote the association of the PH domain with membrane. The higher-affinity binding to PIP2, which apparently promotes a conformational change in the PH domain, may play an important additional role. Boi1 and Boi2 are localized to sites of polarized growth. Whereas the SH3 domain is needed for localization of Boi1 to the neck, the phospholipid-binding portion of the PH domain is important for localization to the bud.


Cancer transmissions and non-transmissions from solid organ transplantation in an Australian cohort of deceased and living organ donors.
Evidence on cancer transmission from organ transplantation is poor. We sought to identify cases of cancer transmission or non-transmission from transplantation in an Australian cohort of donors and recipients. We included NSW solid organ deceased donors 2000-2012 and living donors 2004-2012 in a retrospective cohort using linked data from the NSW Biovigilance Register (SAFEBOD). Central Cancer Registry (CCR) data 1972-2013 provided a minimum one-year post-transplant follow-up. We identified cancers in donors and recipients. For each donor-recipient pair, the transmission was judged likely, possible, unlikely, or excluded using categorization from international guidelines. In our analysis, transmissions included those judged likely, while those judged possible, unlikely, or excluded were non-transmissions. In our cohort, there were 2502 recipients and 1431 donors (715 deceased, 716 living). There were 2544 transplant procedures, including 1828 (72%) deceased and 716 (28%) living donor transplants. Among 1431 donors, 38 (3%) had past or current cancer and they donated to 68 recipients (median 6.7-year follow-up). There were 64 (94%) non-transmissions, and 4 (6%) transmissions from two living and two deceased donors (all kidney cancers discovered during organ recovery). Donor transmitted cancers are rare, and selected donors with a past or current cancer may be safe for transplantation.


inlA premature stop codons are common among Listeria monocytogenes isolates from foods and yield virulence-attenuated strains that confer protection against fully virulent strains.
Previous studies showed that a considerable proportion of Listeria monocytogenes isolates obtained from foods carry a premature stop codon (PMSC) mutation in inlA that leads to production of a truncated and secreted InlA. To further elucidate the role these mutations play in virulence of L. monocytogenes, we created isogenic mutants, including (i) natural isolates where an inlA PMSC was reverted to a wild-type inlA allele (without a PMSC) and (ii) natural isolates where a PMSC mutation was introduced into a wild-type inlA allele; isogenic mutant sets were constructed to represent two distinct inlA PMSC mutations. Phenotypical and transcriptional analysis data showed that inlA PMSC mutations do not have a polar effect on the downstream inlB. Isogenic and natural strains carrying an inlA PMSC showed significantly reduced invasion efficiencies in Caco-2 and HepG2 cell lines as well as reduced virulence in oral guinea pig infections. Guinea pigs were also orally infected with a natural strain carrying the most common inlA PMSC mutation (vaccinated group), followed by challenge with a fully virulent L. monocytogenes strain 15 days postvaccination to probe potentially immunizing effects of exposure to L. monocytogenes with inlA PMSC mutations. Vaccinated guinea pigs showed reduced bacterial loads in internal organs and improved weight gain postchallenge, indicating reduced severity of infections in guinea pigs exposed to natural strains with inlA PMSC mutations. Our data support that (i) inlA PMSC mutations are causally associated with attenuated virulence in mammalian hosts and (ii) naturally occurring virulence-attenuated L. monocytogenes strains commonly found in food confer protective immunity.


The effect of ethylmercury on fetal development and some essential metals levels in fetuses and pregnant female rats.
Ethylmercuric chloride (EtHg), at the dose of 2.5 mg Hg/kg, was administered by gavage every other day to pregnant rats from d 6 to 20 of gestation. On the 21st day of gestation, females were sacrificed to allow the evaluation of embryotoxicity and take the material for analytical determinations. Copper, zinc, iron, and calcium were determined by AAS in liver, kidneys, brain, intestines of fetal and pregnant female rats, as well as in maternal spleen, whole blood, placenta, and fetal carcass.Ethylmercury caused a decrease of the body weight gain during gestation and diminution of relative liver weight of intoxicated females. This compound also induced fetotoxic effects, evidenced by slight diminution of the length as well as the weight of fetuses.It was found that the effect of EtHg on the levels of endogenous metals is different in females and fetuses. In pregnant females, EtHg administration resulted in a significant increase of copper levels in kidneys, liver, and spleen: and in the decrease of zinc concentration in the kidneys, but an increase in placenta and blood compared with pregnant controls. EtHg induced slight decrease of iron concentration in kidneys and intestinal wall of pregnant females. The concentrations of iron in liver and kidney and of zinc in whole blood and liver were lower in control pregnant rats than those in control non-pregnant females. In fetuses of EtHg-exposed mothers, increases in kidney zinc and liver calcium levels were found, whereas tissue copper and iron concentrations were the same as in controls.


Biochemical analysis of the G517V POLG variant reveals wild-type like activity.
The c.1550g→t mutation in the POLG gene causing the G517V substitution has been reported by many groups to be associated with a variety of mitochondrial diseases, including autosomal dominant and recessive forms of ataxia neuropathy, myopathy and microcephaly, progressive external ophthalmoplegia, diabetes, strokes, hypotonia, and epilepsy. However, the variable disease presentation and age of onset raises suspicion of its pathogenicity. Because of the varied reported associated symptoms and request from physicians to address the consequence of this mutation, we have carried out the biochemical analysis of the purified recombinant human DNA polymerase γ protein harboring the G517V substitution. These analyses revealed that the G517V mutant enzyme retained 80-90% of wild-type DNA polymerase activity, in addition to its functional interaction with the p55 accessory subunit. DNA binding by the mutant was also only slightly lower than the wild-type enzyme. Our data suggest that the G517V mutation by itself in pol γ most likely does not have a role in mitochondrial disorders.


Non-Additive Imprecise Image Super-Resolution in a Semi-Blind Context.
The most effective superresolution methods proposed in the literature require precise knowledge of the so-called point spread function of the imager, while in practice its accurate estimation is nearly impossible. This paper presents a new superresolution method, whose main feature is its ability to account for the scant knowledge of the imager point spread function. This ability is based on representing this imprecise knowledge via a non-additive neighborhood function. The superresolution reconstruction algorithm transfers this imprecise knowledge to output by producing an imprecise (interval-valued) high-resolution image. We propose some experiments illustrating the robustness of the proposed method with respect to the imager point spread function. These experiments also highlight its high performance compared with very competitive earlier approaches. Finally, we show that the imprecision of the high-resolution interval-valued reconstructed image is a reconstruction error marker.


Multiple sclerosis and extract of cannabis: results of the MUSEC trial.
Multiple sclerosis (MS) is associated with chronic symptoms, including muscle stiffness, spasms, pain and insomnia. Here we report the results of the Multiple Sclerosis and Extract of Cannabis (MUSEC) study that aimed to substantiate the patient based findings of previous studies. Patients with stable MS at 22 UK centres were randomised to oral cannabis extract (CE) (N=144) or placebo (N=135), stratified by centre, walking ability and use of antispastic medication. This double blind, placebo controlled, phase III study had a screening period, a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase. The primary outcome measure was a category rating scale (CRS) measuring patient reported change in muscle stiffness from baseline. Further CRSs assessed body pain, spasms and sleep quality. Three validated MS specific patient reported outcome measures assessed aspects of spasticity, physical and psychological impact, and walking ability. The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo (29.4% vs. 15.7%; OR 2.26; 95% CI 1.24 to 4.13; p=0.004, one sided). Similar results were found after 4 weeks and 8 weeks, and also for all further CRSs. Results from the MS scales supported these findings. The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of muscle stiffness in MS. This was supported by results for secondary efficacy variables. Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids. No new safety concerns were observed. NCT00552604.


Cross-cultural adaptation and validation of the Mental Health Quality of Life (MHQoL) questionnaire in a Chinese-speaking population with chronic musculoskeletal pain.
The Mental Health Quality of Life (MHQoL) questionnaire is concise and suitable for rapid assessment of CMP (chronic musculoskeletal pain) patients in primary care. However, there is a lack of Chinese versions of the MHQoL. To cross-culturally translate the MHQoL into Chinese and to assess its psychometric properties in Chinese-speaking patients with CMP. The MHQoL was translated into Chinese according to the International Guidelines for the Cross-Cultural Adaptation of Self-Report Measures. 171 CMP patients were recruited to receive the Chinese versions of the MHQoL, SF-36, and HADS tests, and the MHQoL was retested seven days later. The Chinese version of MHQoL had good retest reliability (MHQoL-7D: ICC = 0.971; MHQoL-VAS: ICC = 0.988) and internal consistency (Cronbach's alpha = 0.829). It showed a moderate correlation with the SF-36 total score (r=-0.509); the MHQoL-VAS moderately correlated with the Hospital Anxiety Depression Scale (r=-0.548). The MHQoL-7D showed no correlations with the SF-36's PF (r=-0.083) and BP (r=-0.170), weak correlations with RP (r=-0.284), RE (r=-0.298), and SF (r=-0.380), and moderate-to-strong correlations with GH (r=-0.638), VT (r=-0.480), and MH (r=-0.632). The Chinese version of the MHQoL can be used in clinical practice and research in Chinese-speaking CMP patients.


Validity and reliability of the Perceived Nutrition Environment Measures Survey (NEMS-P) for use in Brazil.
The aim of this study is to evaluate the validity and reliability of the Perceived Nutrition Environment Measures Survey translated and adapted for use in Brazil. Validation of the Perceived Nutrition Environment Measures Survey (NEMS-P) questionnaire. The questionnaires were applied to assess validity and reliability, based on exploratory factor analysis, Cronbach's alpha coefficient and intraclass correlation, with a significance level of 95%. Brazil. Adults over 20 years of age diagnosed with Hypertension were included in the internal validity and reliability test (n=176) and intra-rater reliability (subsample n=35). Factor analysis obtained satisfactory results. Internal consistency was acceptable for most items, with Cronbach's alpha ranging from 0.6 to 0.9. The intra-rater reliability of the subsample was also valid, with intraclass correlation coefficient values ranging from 0.5 to 0.9. This work reveals the usefulness of the instrument to assess the perceived food environment in the Brazilian context, being able to measure what is proposed according to its theoretical model, and reproduces the values when applied to a sample different from its original validation. However, refinement of some questions is suggested. Finally, it demonstrates the possibility of using the entire instrument or each section independently, according to the food environments to be investigated.


Vampire Venom: Vasodilatory Mechanisms of Vampire Bat (Desmodus rotundus) Blood Feeding.
Animals that specialise in blood feeding have particular challenges in obtaining their meal, whereby they impair blood hemostasis by promoting anticoagulation and vasodilation in order to facilitate feeding. These convergent selection pressures have been studied in a number of lineages, ranging from fleas to leeches. However, the vampire bat (Desmondus rotundus) is unstudied in regards to potential vasodilatory mechanisms of their feeding secretions (which are a type of venom). This is despite the intense investigations of their anticoagulant properties which have demonstrated that D. rotundus venom contains strong anticoagulant and proteolytic activities which delay the formation of blood clots and interfere with the blood coagulation cascade. In this study, we identified and tested a compound from D. rotundus venom that is similar in size and amino acid sequence to human calcitonin gene-related peptide (CGRP) which has potent vasodilatory properties. We found that the vampire bat-derived form of CGRP (i.e., vCGRP) selectively caused endothelium-independent relaxation of pre-contracted rat small mesenteric arteries. The vasorelaxant efficacy and potency of vCGRP were similar to that of CGRP, in activating CGRP receptors and Kv channels to relax arteriole smooth muscle, which would facilitate blood meal feeding by promoting continual blood flow. Our results provide, for the first time, a detailed investigation into the identification and function of a vasodilatory peptide found in D. rotundus venom, which provides a basis in understanding the convergent pathways and selectivity of hematophagous venoms. These unique peptides also show excellent drug design and development potential, thus highlighting the social and economic value of venomous animals.


Age-related differences in parathion and chlorpyrifos toxicity in male rats: target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism.
Juvenile rats are more susceptible to the acute toxicity of the phosphorothionate insecticides parathion and chlorpyrifos than are adult rats. Developmental changes in brain acetylcholinesterase and hepatic aliesterase (carboxylesterase), cytochrome P450, and the P450-mediated metabolism of these two phosphorothionate insecticides were investigated in male Sprague-Dawley rats. Specific activities of acetylcholinesterase in cerebral cortex, but not medulla oblongata, and of liver aliesterases increased with age, indicating the presence of both more target esterases and more protective esterases, respectively, in the adult compared to the juvenile animal. Sensitivity of the brain acetylcholinesterase to inhibition by paraoxon and chlorpyrifosoxon, as measured by IC50 values, did not change significantly with age, whereas the hepatic aliesterase sensitivity to inhibition decreased with age. Progressive increases in activities of P450-mediated activation (desulfuration) (6- to 14-fold) and detoxication (dearylation) (2- to 4-fold), as well as concentrations of P450 (7-fold) and protein (2-fold), were observed between neonate and adult hepatic microsomes. Microsomal pentoxyresorufin O-dealkylase activity followed a developmental pattern similar to desulfuration and dearylation, displaying a 16-fold increase between neonates and adults. However, microsomal ethoxyresorufin O-deethylase activity increased until 21 days of age, displaying a 16-fold increase, then decreased in adulthood to a level 10-fold higher than neonates. These results indicate that target enzyme sensitivity is not responsible for age-related toxicity differences, nor is the potential for hepatic bioactivation, whereas lower levels of hepatic aliesterase-mediated protection and P450-mediated dearylation probably contribute significantly to the greater sensitivity of juveniles to phosphorothionate toxicity.


Valganciclovir for symptomatic congenital cytomegalovirus disease.
The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).


Pulse pressure and perioperative stroke.
Central pulse pressure (PP), a marker of vascular stiffness, is a novel indicator of risk for perioperative morbidity including ischemic stroke. Appreciation for the mechanism by which vascular stiffness leads to organ dysfunction along with understanding its clinical detection may lead to improved patient management. Vascular stiffness is associated with increased mortality and neurologic, cardiac, and renal injury in nonsurgical and surgical patients. Left ventricular hypertrophy and diastolic dysfunction along with microcirculatory changes in the low vascular resistance, high blood flow, cerebral and renal vasculature are seen in patients with vascular stiffness. Pulse wave velocity and the augmentation index have higher sensitivity for detecting of vascular stiffness than peripheral PP as the hemodynamic consequences of vascular stiffness are secondary to alterations in the central vasculature. Vascular stiffness alters cerebral autoregulation, resulting in a high likelihood of having a lower limit of autoregulation more than 65 mmHg during surgery. Vascular stiffness may predispose to cerebral hypoperfusion, increasing vulnerability to ischemic stroke, postoperative delirium, and acute kidney injury. Vascular stiffness leads to alterations in cerebral, cardiac, and renal hemodynamics increasing the risk of perioperative ischemic stroke and neurologic, cardiac, and renal dysfunction.


Variation in cold hardiness and carbohydrate concentration from dormancy induction to bud burst among provenances of three European oak species.
Although cold hardiness is known to be a major determinant of tree species distribution, its dynamics and the factors that regulate it remain poorly understood. Variation in cold hardiness and carbohydrate concentration, from dormancy induction until bud burst, were investigated in populations of two deciduous (Quercus robur L. and Quercus pubescens Willd.) and one evergreen (Quercus ilex L.) European oak. Mean cold hardiness values in January were -56, -45 and -27 degrees C for Q. robur, Q. pubescens and Q. ilex, respectively. Soluble carbohydrate concentrations were closely related to instantaneous cold hardiness, estimated by the electrolyte leakage method, whereas total carbohydrate concentration was related to maximum cold hardiness. Both cold hardiness and carbohydrate concentration showed a close linear relationship with temperatures at the location of the sampled population. Our results show that temporal variation in both the inter- and intraspecific cold hardiness in European oaks can be related to variations in the concentrations of soluble carbohydrates and that these relationships appear to be driven by temperature.


Role of surgical and percutaneous drainage in the treatment of abdominal abscesses.
Reviewing our experience with 32 surgically and 13 percutaneously drained abdominal abscesses, we propose the following criteria for computed tomography (CT)-assisted percutaneous drainage: (1) the absence of more than two abscess cavities or loculations; (2) drainage route not traversing bowel, uncontaminated organs, or uncontaminated peritoneal or pleural spaces; (3) the absence of a source of continuous contamination; and (4) the absence of fungi as causative organisms. Of nine abscesses that met these criteria, seven were successfully drained percutaneously. In all abscesses that did not meet the criteria, percutaneous drainage resulted in complications. Of the 32 surgical patients, six would have been candidates for percutaneous drainage according to these criteria. Two of those patients experienced technical complications that might have been prevented by the use of percutaneous drainage. Surgical intervention is the preferred treatment in the majority of patients; however, in properly selected patients, CT-assisted percutaneous drainage is highly successful and can prevent unnecessary morbidity and mortality.


Positive Variables in Adult Patients Who Are at Different Stages of a Naturalistic Psychotherapeutic Treatment.
This study aimed twofold: 1) to study some positive variables (three paths to well-being, life satisfaction, overall well-being and meaning of life) in adult patients who are at different stages of a naturalistic cognitive behavioral psychotherapeutic treatment and 2) to analyze their relationship with the progress during treatment, therapeutic alliance and adherence to treatment from the therapist´s perspective. The sample was composed of 85 outpatients who were in psychotherapeutic treatment. Patients completed the Three Pathways to Well-being Scale, Meaning in Life Questionnaire, Satisfaction with Life Scale, Well-being Index and Symptom Checklist-90-Revised. Therapists completed treatment related data and an opinion survey of patient´s progress, adherence to treatment and therapeutic relationship. Findings showed positive variables to be higher at the final stage of psychotherapy, particularly higher satisfaction with life, engagement, well-being, and presence of meaning in life. Higher positive variables were moderately associated with more progress during treatment according to therapist's perspective; however a low association was found with adherence to treatment and therapeutic relationship. No differences were found in positive variables according the type of prevalent symptoms.


The Deceptively Simple N170 Reflects Network Information Processing Mechanisms Involving Visual Feature Coding and Transfer Across Hemispheres.
A key to understanding visual cognition is to determine "where", "when", and "how" brain responses reflect the processing of the specific visual features that modulate categorization behavior-the "what". The N170 is the earliest Event-Related Potential (ERP) that preferentially responds to faces. Here, we demonstrate that a paradigmatic shift is necessary to interpret the N170 as the product of an information processing network that dynamically codes and transfers face features across hemispheres, rather than as a local stimulus-driven event. Reverse-correlation methods coupled with information-theoretic analyses revealed that visibility of the eyes influences face detection behavior. The N170 initially reflects coding of the behaviorally relevant eye contralateral to the sensor, followed by a causal communication of the other eye from the other hemisphere. These findings demonstrate that the deceptively simple N170 ERP hides a complex network information processing mechanism involving initial coding and subsequent cross-hemispheric transfer of visual features.


Senolytics: Potential for Alleviating Diabetes and Its Complications.
Therapeutics that target cellular senescence, including novel "senolytic" compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventive strategy to reduce the incidence and severity of diabetes complications. The intermittent administration schedule used for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.


Ethanol versus lipopolysaccharide-induced hypothermia: involvement of urocortin.
The urocortin1 (Ucn1) neurons of the mid-brain-localized Edinger-Westphal nucleus (EW) are robustly responsive to ethanol (EtOH) administration, and send projections to the dorsal raphe nucleus (DRN), which contains corticotropin-releasing factor type 2 receptors (CRF2) that are responsive to Ucn1. In addition, the DRN has been shown to be involved in regulation of body temperature, a function greatly affected by EtOH administration. The goal of the present study was to identify the role that the urocortinergic projections from the EW to the DRN have in mediating EtOH-induced and lipopolysaccharide (LPS)-induced hypothermia. Male C57BL6/J mice were used. Groups of mice underwent cannulation of the DRN, and then received i.p. injections of EtOH (2g/kg) or LPS (600 microg/kg or 400 microg/kg), followed by intra-DRN injections of artificial cerebrospinal fluid (aCSF) or anti-sauvagine (aSVG) (55 pmol), a CRF2 antagonist. Separate groups of mice received single intra-DRN injections of Ucn1 (20 pmol), CRF (20 pmol) or aCSF. For all experiments, core temperatures were monitored rectally every 30 min for several hours post-injection. Both EtOH and LPS induced hypothermia, and aSVG significantly attenuated this effect after EtOH; however, there was no significant attenuation of hypothermia after either dose of LPS. Ucn1 injection also caused hypothermia, while CRF injection did not. These data demonstrate that EtOH-induced hypothermia, but not LPS-induced hypothermia, may involve Ucn1 from EW acting at CRF2 receptors in the DRN.


The clinician-information interface.
Technical advances now enable rapid data collection into sophisticated information systems, and the vision of the electronic patient record may soon be a reality. However, despite advances in the human-computer interface, little attention has been given to the structure of the clinical data to be collected in the electronic record. The 'clinician-information interface' embraces the cognitive, analytical, and decision processes that the clinician will need to undergo to capture clinical data in a structured, meaningful, and analyzable form. This paper discusses some of the issues which need to be addressed if the emerging opportunities for a detailed capture of clinical data are to be maximized.


ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.


A neural circuit architecture for angular integration in Drosophila.
Many animals keep track of their angular heading over time while navigating through their environment. However, a neural-circuit architecture for computing heading has not been experimentally defined in any species. Here we describe a set of clockwise- and anticlockwise-shifting neurons in the Drosophila central complex whose wiring and physiology provide a means to rotate an angular heading estimate based on the fly's angular velocity. We show that each class of shifting neurons exists in two subtypes, with spatiotemporal activity profiles that suggest different roles for each subtype at the start and end of tethered-walking turns. Shifting neurons are required for the heading system to properly track the fly's heading in the dark, and stimulation of these neurons induces predictable shifts in the heading signal. The central features of this biological circuit are analogous to those of computational models proposed for head-direction cells in rodents and may shed light on how neural systems, in general, perform integration.


Capture-recapture method for assessing publication bias.
Publication bias is an important factor that may result in selection bias and lead to overestimation of the intervention effect. In this study, the focus was on using capture-recapture method as a statistical procedure which may possibly be a practical means for measuring the amount of publication bias. A systematic review was conducted to estimate the duration of protection provided by hepatitis B vaccine by measuring the anamnestic immune response to booster doses of vaccine and retrieved studies from three separate sources of electronic databases, reference lists of the studies, and conference databases as well as contact with experts and manufacturers. Capture-recapture and some conventional methods such as funnel plot, Begg test, Egger test, and trim and fill method were employed for assessing publication bias. Based on capture-recapture method, completeness of the overall search results was 87.2% [95% CI: 84.6% to 89.0%] and log-linear model suggested 5 [95% CI: 4.2 to 6.2] missing studies. The funnel plot was asymmetric while Begg and Egger tests results were statistically insignificant and trill and fill approach made no change in pooled effect. Capture-recapture method may be a useful practical approach for estimating the number of missing studies which are not usually detected by search strategy. As a result, use of capture-recapture method as an alternative approach could be suggested for estimating the extent of publication bias based on overlapping information rather than mirror image of extreme values on funnel plot.


Molecular imaging of gene expression and efficacy following adenoviral-mediated brain tumor gene therapy.
Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD) along with an optical reporter gene (luciferase). Following intratumoral injection of the vector into orthotopic 9 L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC) gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging for assessment of gene expression and therapeutic efficacy.


Symbol addition by monkeys provides evidence for normalized quantity coding.
Weber's law can be explained either by a compressive scaling of sensory response with stimulus magnitude or by a proportional scaling of response variability. These two mechanisms can be distinguished by asking how quantities are added or subtracted. We trained Rhesus monkeys to associate 26 distinct symbols with 0-25 drops of reward, and then tested how they combine, or add, symbolically represented reward magnitude. We found that they could combine symbolically represented magnitudes, and they transferred this ability to a novel symbol set, indicating that they were performing a calculation, not just memorizing the value of each combination. The way they combined pairs of symbols indicated neither a linear nor a compressed scale, but rather a dynamically shifting, relative scaling.


DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting.
Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset of genes. Many of these 'imprinted' genes in mice and humans are involved in embryonic and extraembryonic growth and development, and some have life-long impacts on metabolism. During mammalian development, the genome undergoes waves of (re)programming of DNA methylation and other epigenetic marks. Disturbances in these events can cause imprinting disorders and compromise development. Multi-locus imprinting disturbance (MLID) is a condition by which imprinting defects touch more than one locus. Although most cases with MLID present with clinical features characteristic of one imprinting disorder. Imprinting defects also occur in 'molar' pregnancies-which are characterized by highly compromised embryonic development-and in other forms of reproductive compromise presenting clinically as infertility or early pregnancy loss. Pathogenic variants in some of the genes encoding proteins of the subcortical maternal complex (SCMC), a multi-protein complex in the mammalian oocyte, are responsible for a rare subgroup of moles, biparental complete hydatidiform mole (BiCHM), and other adverse reproductive outcomes which have been associated with altered imprinting status of the oocyte, embryo and/or placenta. The finding that defects in a cytoplasmic protein complex could have severe impacts on genomic methylation at critical times in gamete or early embryo development has wider implications beyond these relatively rare disorders. It signifies a potential for adverse maternal physiology, nutrition, or assisted reproduction to cause epigenetic defects at imprinted or other genes. Here, we review key milestones in DNA methylation patterning in the female germline and the embryo focusing on humans. We provide an overview of recent findings regarding DNA methylation deficits causing BiCHM, MLID, and early embryonic arrest. We also summarize identified SCMC mutations with regard to early embryonic arrest, BiCHM, and MLID.


Limited promiscuity of HLA-DRB1 presented peptides derived of blood coagulation factor VIII.
The formation of inhibitory antibodies directed against coagulation factor VIII (FVIII) is a severe complication in the treatment of hemophilia A patients. The induction of anti-FVIII antibodies is a CD4(+) T cell-dependent process. Activation of FVIII-specific CD4(+) T cells is dependent on the presentation of FVIII-derived peptides on MHC class II by antigen-presenting cells. Previously, we have shown that FVIII-pulsed human monocyte-derived dendritic cells can present peptides from several FVIII domains. In this study we show that FVIII peptides are presented on immature as well as mature dendritic cells. In immature dendritic cells half of the FVIII-loaded MHC class II molecules are retained within the cell, whereas in LPS-matured dendritic cells the majority of MHC class II/peptide complexes is present on the plasma membrane. Time-course studies revealed that presentation of FVIII-derived peptides was optimal between 12 and 24 hours after maturation but persisted for at least 96 hours. We also show that macrophages are able to internalize FVIII as efficiently as dendritic cells, however FVIII was presented on MHC class II with a lower efficiency and with different epitopes compared to dendritic cells. In total, 48 FVIII core-peptides were identified using a DCs derived of 8 different donors. Five HLA-promiscuous FVIII peptide regions were found - these were presented by at least 4 out of 8 donors. The remaining 42 peptide core regions in FVIII were presented by DCs derived from a single (30 peptides) or two to three donors (12 peptides). Overall, our findings show that a broad repertoire of FVIII peptides can be presented on HLA-DR.


Effect of colchicine on internalization of prolactin in female rat liver: an in vivo radioautographic study.
Binding and internalization of 125I-ovine prolactin into hepatocytes of female rats was visualized by the in vivo radioautographic method (Bergeron, J. J. M., G. Levine, R. Sikstrom, D. O'Shaughnessey, B. Kopriwa, N. J. Nadler, and B. I. Posner, 1977, Proc. Natl. Acad. Sci. USA, 745:051-5055). Receptor-mediated internalization of label was observed into lipoprotein-filled vesicles in the Golgi/bile canalicular region of the hepatocyte. Colchicine treatment had no effect on the internalization of label into the lipoprotein-filled vesicles. However, the location of the radio-labeled lipoprotein-filled vesicles was altered from the Golgi/bile canalicular region to subsinusoidal. Radioactive content of hepatocytes decreased as a function of time after injection of 125I-prolactin; however, colchicine treatment markedly retarded this loss of label. Subcellular fractionation experiments indicated that colchicine treatment led to decreased levels of 125I-prolactin accumulation in microsomes but augmented the accumulation of label in the L fraction. It is concluded that in normal female rats prolactin is internalized into lipoprotein-filled vesicles in the Golgi region before degradation of the hormone. Colchicine treatment accumulates labeled lipoprotein-containing vesicles in a subsinusoidal region and retards hormone catabolism. The labeled vesicles observed after colchicine treatment may correspond to the unique vesicles previously observed in the L fraction and found to be enriched in prolactin receptors (Khan, M. N., B. I. Posner, A. K. Verma, R. J. Khan, and J. J. M. Bergeron, 1981, Proc. Natl. Acad. Sci. USA, 78:4980-4981).


Sensory-Tactile Functional Mapping and Use-Associated Structural Variation of the Human Female Genital Representation Field.
The precise location of the human female genital representation field in the primary somatosensory cortex (S1) is controversial and its capacity for use-associated structural variation as a function of sexual behavior remains unknown. We used a functional magnetic resonance imaging (fMRI)-compatible sensory-tactile stimulation paradigm to functionally map the location of the female genital representation field in 20 adult women. Neural response to tactile stimulation of the clitoral region (vs right hand) identified individually-diverse focal bilateral activations in dorsolateral areas of S1 (BA1-BA3) in alignment with anatomic location. We next used cortical surface analyses to assess structural thickness across the 10 individually most activated vertices per hemisphere for each woman. We show that frequency of sexual intercourse within 12 months is correlated with structural thickness of the individually-mapped left genital field. Our results provide a precise functional localization of the female genital field and provide support for use-associated structural variation of the human genital cortex.SIGNIFICANCE STATEMENT We provide a precise location of the human female genital field in the somatosensory cortex and, for the first time, provide evidence in support of structural variation of the human genital field in association with frequency of genital contact. Our study represents a significant methodological advance by individually mapping genital fields for structural analyses. On a secondary level, our results suggest that any study investigating changes in the human genital field must map the field individually to achieve sufficient precision. Our results pave the way for future research into the plasticity of the human genital cortex as a function of normal or adverse experience as well as changes in pathologic conditions, i.e., sexual dysfunction, sexual deviation, or sexual risk-taking behavior.


In Silico Analysis of Small RNAs Suggest Roles for Novel and Conserved miRNAs in the Formation of Epigenetic Memory in Somatic Embryos of Norway Spruce.
Epigenetic memory in Norway spruce affects the timing of bud burst and bud set, vitally important adaptive traits for this long-lived forest species. Epigenetic memory is established in response to the temperature conditions during embryogenesis. Somatic embryogenesis at different epitype inducing (EpI) temperatures closely mimics the natural processes of epigenetic memory formation in seeds, giving rise to epigenetically different clonal plants in a reproducible and predictable manner, with respect to altered bud phenology. MicroRNAs (miRNAs) and other small non-coding RNAs (sRNAs) play an essential role in the regulation of plant gene expression and may affect this epigenetic mechanism. We used NGS sequencing and computational in silico methods to identify and profile conserved and novel miRNAs among small RNAs in embryogenic tissues of Norway spruce at three EpI temperatures (18, 23 and 28°C). We detected three predominant classes of sRNAs related to a length of 24 nt, followed by a 21-22 nt class and a third 31 nt class of sRNAs. More than 2100 different miRNAs within the prevailing length 21-22 nt were identified. Profiling these putative miRNAs allowed identification of 1053 highly expressed miRNAs, including 523 conserved and 530 novels. 654 of these miRNAs were found to be differentially expressed (DEM) depending on EpI temperature. For most DEMs, we defined their putative mRNA targets. The targets represented mostly by transcripts of multiple-repeats proteins, like TIR, NBS-LRR, PPR and TPR repeat, Clathrin/VPS proteins, Myb-like, AP2, etc. Notably, 124 DE miRNAs targeted 203 differentially expressed epigenetic regulators. Developing Norway spruce embryos possess a more complex sRNA structure than that reported for somatic tissues. A variety of the predicted miRNAs showed distinct EpI temperature dependent expression patterns. These putative EpI miRNAs target spruce genes with a wide range of functions, including genes known to be involved in epigenetic regulation, which in turn could provide a feedback process leading to the formation of epigenetic marks. We suggest that TIR, NBS and LRR domain containing proteins could fulfill more general functions for signal transduction from external environmental stimuli and conversion them into molecular response. Fine-tuning of the miRNA production likely participates in both developmental regulation and epigenetic memory formation in Norway spruce.


Repetitive mild traumatic brain injury-induced neurodegeneration and inflammation is attenuated by acetyl-L-carnitine in a preclinical model.
Repetitive mild traumatic brain injuries (rmTBI) may contribute to the development of neurodegenerative diseases through secondary injury pathways. Acetyl-L-carnitine (ALC) shows neuroprotection through anti-inflammatory effects and via regulation of neuronal synaptic plasticity by counteracting post-trauma excitotoxicity. This study aimed to investigate mechanisms implicated in the etiology of neurodegeneration in rmTBI mice treated with ALC. Adult male C57BL/6J mice were allocated to sham, rmTBI or ALC + rmTBI groups. 15 rmTBIs were administered across 23 days using a modified weight drop model. Neurological testing and spatial learning and memory assessments via the Morris Water Maze (MWM) were undertaken at 48 h and 3 months. RT-PCR analysis of the cortex and hippocampus was undertaken for MAPT, GFAP, AIF1, GRIA, CCL11, TDP43, and TNF genes. Gene expression in the cortex showed elevated mRNA levels of MAPT, TNF, and GFAP in the rmTBI group that were reduced by ALC treatment. In the hippocampus, mRNA expression was elevated for GRIA1 in the rmTBI group but not the ALC + rmTBI treatment group. ALC treatment showed protective effects against the deficits displayed in neurological testing and MWM assessment observed in the rmTBI group. While brain structures display differential vulnerability to insult as evidenced by location specific postimpact disruption of key genes, this study shows correlative mRNA neurodegeneration and functional impairment that was ameliorated by ALC treatment in several key genes. ALC may mitigate damage inflicted in the various secondary neurodegenerative cascades and contribute to functional protection following rmTBI.


A global assessment of stem cell engineering.
Over the last 2 years a global assessment of stem cell engineering (SCE) was conducted with the sponsorship of the National Science Foundation, the National Cancer Institute at the National Institutes of Health, and the National Institute of Standards and Technology. The purpose was to gather information on the worldwide status and trends in SCE, that is, the involvement of engineers and engineering approaches in the stem cell field, both in basic research and in the translation of research into clinical applications and commercial products. The study was facilitated and managed by the World Technology Evaluation Center. The process involved site visits in both Asia and Europe, and it also included several different workshops. From this assessment, the panel concluded that there needs to be an increased role for engineers and the engineering approach. This will provide a foundation for the generation of new markets and future economic growth. To do this will require an increased investment in engineering, applied research, and commercialization as it relates to stem cell research and technology. It also will require programs that support interdisciplinary teams, new innovative mechanisms for academic-industry partnerships, and unique translational models. In addition, the global community would benefit from forming strategic partnerships between countries that can leverage existing and emerging strengths in different institutions. To implement such partnerships will require multinational grant programs with appropriate review mechanisms.


A rare cause of dysphonia.
Although dysphonia is a common complaint among patients seen in an otolaryngology clinic, an autoimmune cause of the problem is less common. Autoimmune disease can be the source of various laryngologic manifestations, but diagnosis depends on a high index of suspicion, careful patient evaluation and testing, and videolaryngoscopy (videostroboscopy if available) to uncover specific identifying findings. This report describes a patient presenting with upper-range vocal difficulties who was found to have early systemic lupus erythematosus.


60-Hz magnetic field exposure effects on the melatonin rhythm and photoperiod control of reproduction.
Adult Djungarian hamsters in long (16 h of light) or short (10 h of light) days for 6 wk were acutely exposed to a 1-G 60-Hz magnetic field (MF) for 15 min 2 h before dark. The nighttime rise in melatonin was delayed and duration reduced in MF-exposed hamsters in both photoperiods compared with sham controls. In a second replicate experiment, MF effects on melatonin rhythm duration were repeated in hamsters in short but not long days, and amplitudes at some clock times differed between the same treatment groups in the two studies. To test the hypothesis that daily MF abbreviates melatonin rhythm duration and induces a long-day reproductive response, adults in shot days were exposed daily to MF. After 3 wk, pineal and serum melatonin rhythms were the same in MF and sham groups; reproduction remained suppressed. Irrespective of acute MF exposure effects on the melatonin rhythm, daily MF treatment does not alter photoperiodic time measurement or the clock mechanism controlling reproduction. Adaption to environmental MF exposures may be part of a normal physiological mechanism that maintains photoperiodic responsiveness in individuals and a seasonal pattern of reproduction.


[Researchers training in the context of the collaborative projects: experiences of Instituto de Medicina Tropical "Alexander von Humbolt", Universidad Peruana Cayetano Heredia].
Research is a main element for human and social development. Under this point of view, it involves particular challenges and opportunities for the so-called "developing countries". An approach for those challenges and opportunities comes from the analysis of two interrelated activities; the training of new researchers and the research development with institutions or researchers which are external to the institution ("collaborative research"). Both activities are essential for the consolidation, widening and updating of the institutional capabilities for scientific production. We present here the experiences of the Instituto de Medicina Tropical "Alexander von Humboldt" of the Universidad Peruana Cayetano Heredia, in relation to the training of new researchers, we discuss the four elements we consider key for this process; the promotion of stimulating environments for research, the proactive identification of fellows, the complementary advice and networks consolidation; and we analyze three successful models of international collaboration for the training of new researchers under different institutional approaches.


Promoting Inuit health through a participatory whiteboard video.
The Inuit community of Rigolet experiences greater rates of self-reported acute gastrointestinal illness (AGI) compared to southern Canada. A whiteboard video tool was collaboratively developed by Rigolet youth, community members, the research team and key regional stakeholders to share public health recommendations for reducing the risk of AGI. The video debuted in Rigolet at a community event in August 2016 and was later provided online for community members and local and regional health departments. Interviews and focus group discussions were used to evaluate the ability of the video to communicate public health information to community members in Rigolet. Community and government viewers reported that the whiteboard video was novel and engaging. Evaluation participants believed the video was suitable for promoting Inuit health because of the use of locally relevant visuals and narrative, which reflect Inuit art and storytelling traditions. Furthermore, participants indicated that the video co-development process was critical to ensuring community relevance of the video. Short-term outcome results suggest the video can reinforce health knowledge and potentially encourage behavioural change. The results suggest this whiteboard video was an effective tool to share information and could increase intention to change behaviours to reduce the risk of AGI in Rigolet. While tools like the whiteboard video are gaining popularity, the participatory approach was used to develop the video, and its use in an Inuit context illustrates its innovation and novelty. This tool may be a useful health promotion tool among Indigenous communities in Canada.


Lipschitz-Killing curvature based expected Euler characteristics for p-value correction in fNIRS.
Functional near-infrared spectroscopy (fNIRS) is a non-invasive imaging approach for measuring brain activities based on changes in the cerebral concentrations of hemoglobin. Recently, statistical analysis based on a general linear model (GLM) has become popular. Here, to impose statistical significance on the activation detected by fNIRS, family-wise error (FWE) rate control is important. However, unlike fMRI, in which measurements are densely sampled on a regular lattice and Gaussian smoothing makes the resulting random field homogeneous, the random fields from fNIRS are inhomogeneous due to the interpolation from sparsely and irregularly distributed optode locations. Thus, tube formula based correction has been proposed to address this issue. However, Sun's tube formula cannot be used for general random fields such as F-statistics. To overcome these difficulties, we employ the expected Euler characteristic approach based on Lipschitz-Killing curvature (LKC) to control the family-wise error rate. We compared this correction method with Sun's tube formula for t-statistics to confirm the existing method. Based on this comparison, we show that covariance estimation should be modified to consider channel-wise least-square residual correlation. These new results supplement the existing tool of statistical parameter mapping for fNIRS.


Rat plasma murinoglobulin: isolation, characterization, and comparison with rat alpha-1- and alpha-2-macroglobulins.
Murinoglobulin, a newly identified mouse plasma protein with trypsin-protein esterase activity (Saito, A. & Sinohara, H. (1985) J. Biol. Chem. 260, 775-781), was also found in rat plasma and purified to apparent homogeneity. The serum level of rat murinoglobulin was 14.1 mg/ml, amounting to 1/3 of the total serum globulin fraction. Rat murinoglobulin was a monomeric glycoprotein (Mr = 210,000) containing 12% carbohydrate. Rat plasma contained two isoforms of murinoglobulin, termed I and II, which showed complete immunological identity on double diffusion analysis using rabbit antiserum raised against isoform I or II. These antisera also showed partial cross-reactivity towards mouse murinoglobulin and rat alpha-1-macroglobulin but not towards rat or human alpha-2-macroglobulin. The chemical compositions, peptide mapping patterns and electrophoretic mobilities of the two isoforms resembled each other but clearly differed from those of rat alpha-1- or alpha-2-macroglobulin. Rat murinoglobulin inhibited the proteolytic activity of trypsin towards casein and remazol brilliant blue hide powder. The inhibition as to the latter substrate was greater than that as to the former. When molar ratios of inhibitor to trypsin were low, murinoglobulin and the two alpha-macroglobulins stimulated the amidolytic activity of trypsin towards a synthetic substrate. At higher ratios, however, murinoglobulin, but not the alpha-macroglobulins, inhibited the same activity. The trypsin-protein esterase activity of murinoglobulin and the two alpha-macroglobulins was impaired by a molar excess of soybean trypsin inhibitor. Murinoglobulin and the two alpha-macroglobulins were inactivated by methylamine with a concomitant unmasking of the thiol group. Murinoglobulin was much more sensitive to soybean trypsin inhibitor and methylamine than the two alpha-macroglobulins.


A deep learning-based approach to diagnose mild traumatic brain injury using audio classification.
Mild traumatic brain injury (mTBI or concussion) is receiving increased attention due to the incidence in contact sports and limitations with subjective (pen and paper) diagnostic approaches. If an mTBI is undiagnosed and the athlete prematurely returns to play, it can result in serious short-term and/or long-term health complications. This demonstrates the importance of providing more reliable mTBI diagnostic tools to mitigate misdiagnosis. Accordingly, there is a need to develop reliable and efficient objective approaches with computationally robust diagnostic methods. Here in this pilot study, we propose the extraction of Mel Frequency Cepstral Coefficient (MFCC) features from audio recordings of speech that were collected from athletes engaging in rugby union who were diagnosed with an mTBI or not. These features were trained on our novel particle swarm optimised (PSO) bidirectional long short-term memory attention (Bi-LSTM-A) deep learning model. Little-to-no overfitting occurred during the training process, indicating strong reliability of the approach regarding the current test dataset classification results and future test data. Sensitivity and specificity to distinguish those with an mTBI were 94.7% and 86.2%, respectively, with an AUROC score of 0.904. This indicates a strong potential for the deep learning approach, with future improvements in classification results relying on more participant data and further innovations to the Bi-LSTM-A model to fully establish this approach as a pragmatic mTBI diagnostic tool.


Induction of the chromosomal translocation t(14;18) by targeting the BCL-2 locus with specific binding I-125-labeled triplex-forming oligonucleotides.
Triplex-Forming oligonucleotides (TFO) bind sequence-specific to the DNA double helix in-vitro and in-vivo and are a promising tool to manipulate genes or gene regulatory elements. TFO as a carrier molecule for short-range particle emitter such as Auger-Electron-Emitters (AEE) bear the potential to introduce radiation-induced site-specific complex DNA lesions, which are known to induce chromosomal translocations. We studied gene expression, translocation frequency and protein expression in SCL-II cells after transfection with the AEE Iodine-125 (I-125) labeled TFO-BCL2 targeting the human BCL2 gene. The TFO-BCL2 binds to the BCL2 gene in close proximity to a known major-breakage-region (mbr). SCL-II cells were transfected with I-125 labeled TFO and stored for decay accumulation. Monitoring of BCL2 translocations was done with the Fluorescence-In-Situ-Hybridization (FISH) method. The utilized FISH probes were designed to detect a t(14;18) translocation of the BCL2 gene, which is a common translocation leading to an overexpression of BCL2 protein. Analysis of BCL2 gene expression levels was done via quantitative Real-Time PCR. Verification of gene expression on the protein level was analyzed by Western blotting. The relative gene expression of BCL2 in I-125-TFO-BCL2 transfected cells showed a significant up-regulation when compared to controls. Analysis of the BCL2 t(14;18) translocation frequency revealed a significant 1.8- to 2-fold increase when compared to control cells. This 2-fold increase was not reflected on the protein level. We conclude that I-125 decays within the BCL2 gene facilitate the t(14;18) chromosomal translocation in the SCL-II cells and that the increased frequency contributes to the observed overall enhanced BCL2 gene expression.